Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, and multiple sclerosis, are thought to arise from abnormalities of innate or adaptive immune responses. Autoimmune diseases are often difficult to diagnose, as the symptoms can be typical of other conditions and quite vague, such as musculoskeletal complaints and pain, headaches or dizziness. No available blood test can accurately exclude the possibility of an autoimmune disease in a subject with these symptoms. At best, a battery of tests and a period of observation are usually required to establish that a patient does in fact have an autoimmune disorder. Thus, a single test that could readily exclude the possibility of an autoimmune disease would allow physicians to focus their efforts on patients who have the greatest likelihood of serious disease. Using microarray technology, we have compared differences in gene expression in peripheral blood mononuclear cells among individuals with four distinct autoimmune diseases, normal control individuals before and after immunization, and individuals with other chronic diseases. Surprisingly, we find that each individual with autoimmune disease has a common gene expression signature that is independent of the specific autoimmune disease but is totally distinct from the normal immune response and is not observed in individuals with other chronic diseases. Based upon these observations, we have developed a simple test for excluding the possibility that a subject has an autoimmune disorder. The main advantage of this test is that it is a quicker and more accurate test than those currently available. This test has thus far predicted autoimmune patients from normal patients with 100 percent accuracy. The first goal of this proposal is to collect gene expression data from a sufficient number of individuals to design a test with optimal predictive power. The second goal is to validate the test by examining a cohort of individuals who do not yet carry a clear-cut diagnosis of an autoimmune disease. Long-term goals are to use results from microarray experiments to develop tests that have predictive value for the therapeutic management of individuals with autoimmune diseases. These include tests that classify diseases, predict severity, and predict the best therapeutic options.